Preparation of controlled release skeletal muscle relaxant dosage forms

ABSTRACT

The present invention is directed to a method of preparing an extended release pharmaceutical composition comprising cyclobenzaprine, comprising coating inert particles with a cyclobenzaprine-containing the drug layering composition and a seal coating composition to form IR beads, then coating the IR beads with an extended release coating to form ER beads.

This application claims priority to U.S. Provisional Application Ser.No. 61/074,464, filed Jun. 20, 2008, the disclosure of which is hereinincorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The present invention is directed to methods for preparing oral dosageforms of skeletal muscle relaxants, for example cyclobenzaprine. A majorobjective of developing and commercializing controlled release dosageforms for indications such as cardiovascular diseases, chronic pain,relief of muscle spasm and associated symptoms especially in the elderlyis to deliver the drug so as to maintain the drug at therapeuticallyeffective concentrations over an extended period of time, therebyenhancing patient compliance and therapeutic efficacy, thereby reducingboth cost of treatment and side effects.

BACKGROUND OF THE INVENTION

Many therapeutic agents are most effective when made available at aconstant rate at or near the absorption site. The absorption oftherapeutic agents thus made available generally results in desiredplasma concentrations leading to maximum efficacy and minimum toxic sideeffects. Much effort has been devoted to developing matrix tablet basedand multi-particulate capsule based drug delivery systems for oralapplications.

U.S. Pat. No. 4,839,177 to Colombo, et al, assigned to Jagotec A G,refers broadly to controlled release of active substances includingmedicaments and any type of substance which is to be released at acontrolled rate into an aqueous fluid. The patent is directed to asystem for the controlled-rate release of active substances consistingof a deposit core comprising an active substance and at least one of (a)a polymeric material having a high degree of swelling on contact withwater and a gellable polymeric material or (b) a single polymericmaterial having both swelling and gelling properties, and a supportplatform applied to the deposit core wherein the support platformconsists of a water insoluble polymeric material.

U.S. Pat. No. 4,851,228 and U.S. Pat. No. 4,968,507, both to Zentner etal., assigned to Merck & Company, refer to a multi-particulate osmoticpump for the controlled release of a pharmaceutically active agent, eachosmotic pump element consisting essentially of a core containing anactive agent and a rate controlling water insoluble wall comprising asemi-permeable polymer and at least one pH insensitive pore formingadditive dispersed throughout the wall. U.S. Pat. No. 4,590,062 to Jangassigned to Tech Trade Corporation and U.S. Pat. No. 4,882,167 to Jang,are directed to a compressed product containing an active produced bydry blending with a matrix combination of a hydrophobic polymer (e.g.ethylcellulose) and a wax, fatty acid, neutral lipid or combinationthereof.

U.S. Pat. No. 4,996,047 to Kelleher, assigned to Richardson-Vicks, isdirected to an oral pharmaceutical composition in unit dosage form ofion-exchange resin particles having a pharmacologically active drugbound thereto wherein the drug-resin complex particles have been coatedwith a water-impermeable diffusion barrier to provide controlled releaseof the active drug. U.S. Pat. No. 5,120,548 to McClelland et al.,assigned to Merck & Company, is directed to a controlled release drugdelivery device comprising a composition of a polymer which swells uponexposure to an aqueous environment, a plurality of controlled releaseswelling modulators, at least one active agent and either a waterinsoluble polymer coating surrounding the composition or a microporouswall surrounding the composition. U.S. Pat. No. 5,350,584 to McClellandet al., assigned to Merck & Company, relates to a process for theproduction of microcrystalline cellulose-free multiparticulatescomprising a medicament and a charged resin. The resulting spheronizedbeads can be used in certain controlled release dosage forms.

U.S. Pat. No. 5,366,738 to Rork et al., assigned to Merck & Company, isdirected to a drug delivery device for controlled release of an activeagent. The drug delivery device includes a compressed core with anactive agent and a polymer which forms gelatinous microscopic particlesupon hydration and a water insoluble, water impermeable polymericcoating comprising a polymer and plasticizer which surrounds and adheresto the core.

U.S. Pat. No. 5,582,838 to Rork et al., assigned to Merck & Company, isrelated to a drug delivery device for the controlled release of abeneficial agent. The drug delivery device includes a compressed corehaving at least two layers: at least one layer is a mixture of abeneficial agent and a polymer which forms microscopic polymer gel beadsupon hydration and at least one outer layer comprises a polymer whichforms microscopic polymer gel beads upon hydration. A water insoluble,water impermeable coating is applied to the core and the coating hasapertures exposing between about 5-75% of the core surface.

U.S. Pat. No. 5,874,418 to Stella et al., assigned to Cydex, is directedto a pharmaceutical composition comprising a carrier and a mixture of asulfoalkyl ether-cyclodextrin and a therapeutic agent wherein a majorportion of the therapeutic agent is not complexed to the sulfoalkylether-cyclodextrin derivative. Delayed, sustained or controlled releaseformulations are also described wherein the pharmaceutical core iscoated with a film coating comprising a file forming agent and a poreforming agent. U.S. Pat. No. 5,882,682 to Rork et al., assigned to Merck& Company, is directed to a drug delivery process including the steps ofpreparing a uniform mixture of a polymer which forms gelatinousmicroscopic particles upon hydration, the beneficial agent and otherexcipients used in the preparation of the core; compressing the mixtureinto cores; coating the entire core with a water insoluble, waterimpermeable polymeric coating including a polymer and a plasticizer; andforming apertures through the coating.

U.S. Pat. No. 5,952,451 to Zhao, assigned to Guilford Pharmaceuticals isdirected to a process for preparing high molecular weightpoly(phosphoester) compositions comprising a biologically activesubstance and a poly(phosphoester) and the high molecular weightcompositions produced thereby. The polymers so produced are useful inprolonged released drug delivery systems. U.S. Pat. No. 6,004,582 toFaour et al., assigned to Laboratorios Phoenix U.S.A., is directed to amulti-layered osmotic device comprising a compressed core including afirst active agent and an osmotic agent, a semi-permeable membranesurrounding the core and having a preformed passageway therein whereinthe membrane is permeable to a fluid in the environment of use andsubstantially impermeable to the first active agent. The semi-permeablemembrane preferably consists essentially of cellulose acetate andpoly(ethylene glycol). The external coat can includepoly(vinylpyrrolidone) and poly (ethylene glycol) and can furtherincludes materials such as HPMC, ethylcellulose, hydroxylethylcellulose, CMC, dimethylaminoethyl methacrylate-methacrylic acidester copolymer, ethyl acrylate-methyl methacrylate copolymer, andcombinations thereof.

WO 99/18937 to Kleinbart et al., (Merck & Company), is directed to acomposition comprising a pharmaceutically effective amount ofcyclobenzaprine and calcium phosphate dibasic hydrous, wherein thetablet releases most of the active component within an hour. WO 99/30671to Ron, is directed to an oral delivery vehicle including an aspectedparticle comprising a pharmaceutically active component and excipientswherein the vehicle is formulated to provide controlled delivery of thepharmaceutically active component. The vehicle may further contain acoating to provide sustained drug delivery to the particle. WO 98/53802to Faour et al., (Laboratorios Phoenix USA), is directed to amulti-layered osmotic device that is capable of delivering a firstactive agent in an outer lamina to one environment of use and a secondactive agent in the core to another environment of use. An erodiblepolymer coat between an internal semipermeable membrane and a secondactive agent-containing external coat comprisespoly(vinylpyrrolidone)-vinyl acetate) copolymer. The active agent in thecore is delivered through a pore containing an erodible plug.

WO 98/18610 to Van Lengerich, is directed to particles containing anactive agent, which provide controlled release of the active ingredientwithout substantial destruction of the matrix material. A release-ratecontrolling component is incorporated in a matrix to control therate-release of the encapsulant from the particles. A hydrophobiccomponent or a high water binding capacity component may be used forextending the release time. Release properties may also be controlled byprecoating the encapsulant and/or coating the particles with afilm-forming component. WO 98/06439 to Oedemoed, (Osteotech), isdirected to a composition comprising a biologically active agentencapsulated in a matrix comprising a polyether ester copolymer, such aspolyethylene glycol terephthalate/polybutylene-terephthalate copolymer.The polyether ester copolymer protects the active agent from degradationand thereby facilitates the drug delivery.

Cyclobenzaprine hydrochloride, a skeletal muscle relaxant, is acentrally acting drug which reduces or abolishes excessive tonic muscleactivity in hypertonic as opposed to hyperphasic disorders. Flexeril® isan immediate release cyclobenzaprine composition in the form of a coatedtablet. Flexeril tablets are prepared by mixing and compressing thecyclobenzaprine and excipients (lactose, starch, magnesium stearate, andcoloring agents), then coating the resulting tablet with awater-soluble, pharmaceutically acceptable polymer solution(hydroxypropylcellulose/hydroxypropylmethylcellulose). Flexeril® tabletsare available in either 5 mg or 10 mg dosages, and are typicallyadministered three times a day to produce the desired therapeuticeffect. Flexeril IR (immediate release) tablets containing 10 mg ofcyclobenzaprine HCl are administered three times a day to relieveskeletal muscle spasm of local origin without interfering with musclefunction. The oral administration thrice daily is an issue of patientcompliance, especially with the elderly. Hence, there is a need formodified release skeletal muscle relaxant suitable for a singleadministration. More particularly, there is a need for modified release(MR) cyclobenzaprine hydrochloride dosage forms, 15 and 30 mg, whichwould substantially minimize intersubject variability and improve thequality of life, especially in the elderly population.

U.S. Patent App. Publ. No. 2005/0106247 describes a process forpreparing oral dosage forms of cyclobenzaprine in which drug-layeredbeads are prepared by coating an inert particle with a solution ofcyclobenzaprine and an optional polymeric binder, then coating thedrug-layered beads with a water insoluble polymer or a mixture of awater insoluble and a water-soluble polymer to form an extended releasecoating. The resulting extended release beads were then filled into agelatin capsule. These extended release cyclobenzaprine capsules areavailable in 15 mg or 30 mg dosages, and are intended to be administeredonce a day to produce the therapeutic effect provided by three times aday administration of Flexeril® tablets.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: coating about 20-25mesh inert particles with a drug layering composition comprisingcyclobenzaprine or a pharmaceutically acceptable salt, solvate, and/orester thereof, and a pharmaceutically acceptable solvent, e.g., anaqueous organic solvent; drying the coated inert particles, therebyforming drug layered beads; coating the drug layered beads with a sealcoating composition comprising a pharmaceutically acceptable watersoluble polymer and water; drying the coated drug layered beads, therebyforming IR beads; and coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads.

In another embodiment, the present method is directed to a method ofpreparing a pharmaceutical composition comprising coating about 20-25mesh inert particles with an about 25 wt. % solids content drug layeringcomposition comprising cyclobenzaprine or pharmaceutically acceptablesalts, solvates, and/or esters thereof, and an aqueous organic solvent;drying the coated inert particles, thereby forming drug layered beads;coating the drug layered beads with an about 8-10 wt. % solids contentseal coating composition comprising a pharmaceutically acceptable watersoluble polymer and water; drying the coated drug layered beads, therebyforming IR beads (e.g., drug load: 25% w/w); coating the IR beads withan about 6 wt. % solids content ER coating composition comprising apharmaceutically acceptable water-insoluble polymer and an optionalplasticizer; drying the coated IR beads under an atmosphere having a dewpoint ranging from about 5-20° C., thereby forming ER beads; andoptionally curing the sieved ER beads at about 60° C. for up to about 4hours, under an atmosphere having a dew point ranging from about 5-20°C.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in further detail with reference to theaccompanying Figures wherein:

FIG. 1 shows the proposed target release profile for cyclobenzaprinehydrochloride MR (modified release) capsules, 15 and 30 mg.

FIG. 2 shows the simulated Day 1 plasma level following dosing of 1×10mg Flexeril® given 3 times a day and 1×30 mg cyclobenzaprine HCl MRcapsule given once-daily.

FIG. 3 shows the drug release profiles for cyclobenzaprine HCl ER(extended release) beads of Example 3.

FIG. 4 compares the drug release profiles as a function of membranecoating of Example 4.

FIG. 5 shows the drug release profiles for cyclobenzaprine HCl ER beadsof Example 4 stored in induction sealed HDPE bottles on acceleratedstability.

FIG. 6 shows the drug release profiles for 30 mg cyclobenzaprine HCl MRcapsules of Example 5.

FIG. 7 shows the plasma levels for cyclobenzaprine HCl MR capsules, 15and 30 mg of Example 6.

FIG. 8 shows a flow diagram of a cyclobenzaprine MR capsule productionprocess.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited herein are incorporated by reference in theirentirety for all purposes. The citation of any document is not to beconstrued as an admission that it is prior art with respect to thepresent invention.

The terms “drug”, “active”, “active pharmaceutical ingredient”, etc. areused interchangeably.

All references to a particular drug or active herein includepharmaceutically acceptable salts, solvates, esters, isomers, etc.thereof unless expressly indicated otherwise.

In its various embodiments, the present invention is directed to methodsof preparing pharmaceutical compositions as described herein.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: (a) coating about20-25 mesh inert particles with a drug layering composition comprisingcyclobenzaprine or a pharmaceutically acceptable salt, solvate, and/orester thereof, and an aqueous organic solvent; b) drying the coatedinert particles, thereby forming drug layered beads; c) coating the druglayered beads with a seal coating composition comprising apharmaceutically acceptable water soluble polymer and water; d) dryingthe coated drug layered beads, thereby forming IR beads; e) coating theIR beads with an ER coating composition comprising a pharmaceuticallyacceptable water-insoluble polymer; f) drying the coated immediaterelease beads under an atmosphere having a dew point ranging from about5-20° C., thereby forming ER beads. In yet another embodiment, thepresent invention further comprises curing the ER beads from step f),above at about 60° C. under an atmosphere having a dew point rangingfrom about 5-20° C. The curing process may be carried out for about 12hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, orabout 2 hours.

Pharmaceutically acceptable inert particles are first coated with a druglayering composition. Non-limiting examples of suitable pharmaceuticallyacceptable particles include sugar spheres or beads (e.g., Celphere®),cellulose spheres, silicon dioxide spheres, acidic buffer particles,alkaline buffer particles, or the like, having a suitable particle sizedistribution, e.g., about 20-25 mesh. In one embodiment, the inertparticles are sugar beads (non-pareil seeds) having a particle size ofabout 20-25 mesh.

The drug layering composition comprises the drug (e.g., cyclobenzaprineand pharmaceutically acceptable salts, solvates, and/or esters thereof)dissolved or dispersed in an aqueous organic solvent. Non-limitingaqueous organic solvents include aqueous ketones or aqueous alcohols,for example aqueous acetone. In one embodiment, the aqueous organicsolvent is 1:1 water/acetone, and the drug is cyclobenzaprinehydrochloride, e.g., dissolved to a solids content of about 25 wt. %.

In other embodiments, the drug layering composition further comprises anoptional binder, for example a pharmaceutically acceptable water solublepolymer such as polyvinylpyrrolidone (PVP), carboxyalkylcelluloses,polyethylene oxide, polysaccharides such as dextran, corn starch,cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) andhydroxypropylcellulose. In one embodiment, the drug layering compositioncontains a binder as described herein. In another embodiment, the druglayering composition does not contain a binder.

The coating weight of the drug layering composition (i.e., the weight ofthe solids dissolved in the aqueous organic solvent deposited on theinert particles, expressed as a percentage weight increase of the beadsafter coating and drying) can vary depending on the desired dosage ofthe drug, and can range from about 5 wt. % to about 30 wt. %, includingabout 5 wt. %, about 10 wt. %, about 15 wt. %, about 20 wt. %, about 25wt. %, or about 30 wt. %. In one embodiment, the coating weight of thedrug layering composition is about 25 wt. %.

The drug layering composition can be applied by any suitable method,including a continuous or batch type fluid bed coating apparatus such asthose manufactured by Glatt. For example, the drug layering can becarried out on a Glatt GPCC 120 equipped with an 18 inch bottom sprayWurster insert (e.g., using a type “C” air distribution plate with 1.5mm holes at the center and 2.0 mm holes that the outer circumference, ora type “D” air distribution plate with 2.0 mm holes at the center and3.5 mm holes at the outer circumference). The fluid bed coatingapparatus can be operated under any suitable conditions which minimizeagglomeration of the drug layered beads during coating, and whichprovide the coating weight described herein. For example, the partitionheight from the distribution plate can be about 53 mm, ranging fromabout 45 mm to about 55 mm. In one embodiment, the partition height fromthe distribution plate is about 53±2 mm. Likewise, the rate at which thedrug layering composition is sprayed onto the inert particles and theprocess air volume (and other operating parameters) can be modified,e.g. to obtain the desired coating weight. For example, in oneembodiment the spray rate ranges from 100 g/min to about 400 g/min, andthe process air volume ranges from about 800-1500 CFM.

The dried drug layered beads can then be coated with a seal coatingcomposition, for example to improve the mechanical strength of the druglayered beads. Any suitable seal coating composition can be used whichdoes not interfere with the properties of the extended release coatingadded in subsequent steps. Suitable seal coating compositions comprise apharmaceutically acceptable water-soluble polymer dissolved or dispersedin water. Non-limiting examples of water-soluble polymers includepolyethylene glycol, hydroxypopylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose,polyvinylpyrrolidone and mixtures thereof. In one embodiment, thewater-soluble polymer is hydroxypropylmethylcellulose (e.g., Opadry®Clear). The solids content of the seal coating composition can rangefrom about 2 wt. % to about 10 wt. %, for example about 2 wt. %, about 3wt. %, about 4 wt. %, about 5 wt. %, about 6 wt. %, about 7 wt. %, about8 wt. %, about 9 wt. %, or about 10 wt. %. In one embodiment, the solidscontent of the seal coating composition is about 8-10 wt. %. In anotherembodiment, the solids content of the seal coating composition is about8 wt. %.

The seal coating step can be carried out, for example, using a fluid bedcoating apparatus as described herein, and can be dried under suitableconditions, for example in a fluid bed coating apparatus undertemperature conditions as described herein. For example, the sealcoating composition can be applied to a spray rate of about 200 g/min,and dried at a product temperature ranging from about 35° C. to about60° C. In one embodiment, the product temperature is about 42° C. Theresulting seal coated drug layered beads are then referred to as“immediate release” (IR) beads because the drug is released essentiallyimmediately upon dissolution or administration.

After layering with the drug layering composition, the resulting druglayered beads are dried to remove the aqueous organic solvent. Anysuitable drying conditions can be used which do not degrade the drug(e.g. cyclobenzaprine or its pharmaceutically acceptable salts,solvates, and/or esters). For example, the drug layered beads can bedried in the coating apparatus (e.g., a fluid bed coating apparatus suchas a Glatt fluid bed coater equipped with a Wurster insert). Suitabledrying temperatures are approximately 50° C., for example in the rangeof about 45° C. to about 55° C.

If desired, after drying the IR beads can optionally be “sized” toremove fines (i.e., very fine particles) or agglomerates. For examplethe IR beads can be “sieved” with 14-mesh and 24-mesh screens to removeundersized and oversized particles.

The IR beads are then coated with an “extended release” (ER) coatingcomposition comprising a pharmaceutically acceptable water insolublepolymer. Non-limiting examples of suitable pharmaceutically acceptablewater-insoluble polymers include waxes, water-insoluble cellulosederivatives (e.g. ethylcellulose, ethers of cellulose, esters ofcellulose, cellulose acetate, cellulose butyrates, cellulose propionate,ethyl cellulose mixed cellulose esters, etc), high molecular weighthydroxypropyl methylcellulose with a viscosity of a 2 wt. % aqueoussolution of 3000-5600 cps or higher, acylated polysaccharides,polyurethanes, polyvinyl acetate (e.g., Kollicoat SR30D from BASF),polyacrylate and polymethacrylate polymers and derivatives, neutralcopolymers comprising repeating units of ethyl acrylate and/ormethylmethacrylate, pH-insensitive ammonio methacrylic acid copolymers,copolymers of acrylic and methacrylic acid esters with quaternaryammonium groups, such as Eudragit NE, RS, RS30D, RL or RL30D and thelike, and combinations thereof. The water-insoluble polymers in the ERcoating compositions can be plasticized or unplasticized.

In another embodiment of the present invention, the ER coatingcomposition comprises a water insoluble polymer and a plasticizer.Non-limiting examples of suitable plasticizers include glycerol andesters thereof (e.g., acetylated mono- or diglycerides includingcommercially available Myvacet® 9-45), glyceryl monostearate, glyceryltriacetate, glyceryl tributyrate, dibutyl phthalate, diethyl phthalate,dimethyl phthalate, dioctyl phthalate, acetylcitric acid tributyl ester,acetylcitric acid triethyl ester, tributyl citrate, acetyltributylcitrate, triethyl citrate, glyceroltributyrate; diethyl sebacate,dibutyl sebacate, dibutyl adipates, dibutyl azelates, dibutyl benzoates,chlorobutanol, polyethylene glycols, vegetable oils, diethyl fumarate,diethyl malates, diethyl oxalate, dibutyl succinate, dibutyl butyrate,cetyl alcohol esters, diethyl malonate, castor oils, polysorbates,N-butylbenzenesulfonamide, N-methylpyrrolidone, and mixtures thereof.The plasticizer may comprise about 3 to 30 wt. % (for example about 3wt. %, about 5 wt. %, about 10 wt. %, about 15 wt. %, about 20 wt. %,about 25 wt. %, or about 30 wt. %) and more typically about 10 to 25 wt.% of the ER coating (relative to the amount of water-insoluble polymer).

The ER coating composition can be in the form of a solution (e.g., ofthe water-insoluble polymer and optional plasticizer in a suitablepharmaceutically acceptable solvent), or in the form of a dispersion(e.g., of the water-insoluble polymer and/or optional plasticizer in asuitable pharmaceutically acceptable liquid). In one embodiment, the ERcoating composition comprises an aqueous dispersion of ethylcelluloseand a plasticizer (e.g., dibutyl sebacate). In another embodiment, theER coating composition comprises a solution of ethylcellulose (e.g.,Ethocel Premium Standard 10 cps) and a plasticizer (e.g., diethylphthalate) in acetone/water. In a further embodiment, the ER coatingcomprises a solution of ethylcellulose and diethyl phthalate in 98:2acetone:water. In yet another embodiment, the ER coating contains about90% ethylcellulose and about 10 wt. % diethyl phthalate. In still yetanother embodiment, the ER coating composition comprises a solution ofethylcellulose and diethyl phthalate in a acetone:water mixturecomprising about 85 wt % to 98 wt. % acetone and 15 wt. % to 2 wt. %water including weight ratios of acetone/water of about 88/12, about90/10, about 92/8, and about 95/5 to about 98/2. In still a furtherembodiment, the ER coating composition comprises a solution ofethylcellulose and diethyl phthalate in about 98:2 acetone:water.

The solids content of the ER coating composition can vary from about 5wt. % to about 10 wt. %. In one embodiment, the solids content of the ERcoating composition is about 6-7 wt. %. In yet another embodiment, thesolids content of the ER coating composition is about 6.5 wt. %. Instill another embodiment, the ER coating composition comprises asolution of ethylcellulose and diethyl phthalate in acetone/water,having about a 6 wt. % solids content.

The ER coating composition is prepared by stirring a mixture of apharmaceutically acceptable water-insoluble polymer as described herein(e.g. ethylcellulose), optionally a plasticizer as described herein, anda pharmaceutically acceptable solvent (as described herein, e.g. anaqueous organic solvent). In one embodiment, the ER coating compositionis prepared by stirring a mixture of a pharmaceutically acceptablewater-insoluble polymer (e.g. ethylcellulose), a plasticizer (e.g.diethyl phthalate), and a pharmaceutically acceptable solvent (e.g.acetone/water), wherein the resulting solution is stirred after theaddition of the plasticizer for up to 8 hours, but not less than onehour (e.g., for about 1-2 hours, for about 2-6 hours, for about 3-4hours, or about 1 hour) to insure proper homogenization.

The ER composition coating step can be carried out, for example using afluid bed coating apparatus at a spray rate of about 75-700 g/min, usinga process air volume of 700-1500 CFM. The ER coated beads can be driedunder suitable conditions, for example in the fluid bed coatingapparatus under temperature and humidity conditions as described herein,for example at a product temperature of 27-40° C. (typically 33-34° C.at steady state) and dew point of about 5-20° C. (including about 5° C.,about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about11° C., about 12° C., about 13° C., about 14° C., about 15° C., about16° C., about 17° C., about 18° C., about 19° C., or about 20° C.,inclusive of all values, ranges, and subranges therebetween; typically10° C. at steady state).

If desired, after drying the ER beads can optionally be “sized” toremove fines (i.e., very fine particles) or agglomerates. For examplethe ER beads can be “sieved” with 14-mesh and 24-mesh screens to removeundersized and oversized particles.

Optionally, curing or further drying of the ER beads may be carried out,for example, in a conventional oven, more particularly in a tray-dryingoven. Other drying or curing methods known in the art can also be used(e.g., drying under a gas stream). In one embodiment, the ER beads aredried at a dew point determined to give a desired drug release profile(e.g., after 2 hours, no more than about 40% of the total active isreleased; after 4 hours, from about 40-65% of the total active isreleased; after 8 hours, from about 60-85% of the total active isreleased; and optionally after 12 hours, from about 75-85% of the totalactive is released). In another embodiment, the ER beads are dried at adew point of about 5-20° C. (including about 5° C., about 6° C., about7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12°C., about 13° C., about 14° C., about 5° C., about 16° C., about 17° C.,about 18° C., about 19° C., or about 20° C., inclusive of all values,ranges, and subranges therebetween), for example about 6-17° C. or about8-10° C. Any properly equipped drying apparatus can be used for dryingunder dew-point controlled conditions. For example, a conditioning unitthat monitors and adjusts dew point can be added to the dryingapparatus. Another suitable method involves using a drying gas driedusing any drying/de-humidifying apparatus, where the drying gas is driedto the desired dew point.

A lower dew point correlates with drier air. Thus, alternatively, thedrying process may be monitored and adjusted to maintain a desiredrelative humidity. In another embodiment, the ER beads are dried at arelative humidity determined to give a desired drug release profile(e.g., after 2 hours, no more than about 40% of the total active isreleased; after 4 hours, from about 40-65% of the total active isreleased; after 8 hours, from about 60-85% of the total active isreleased; and optionally after 12 hours, from about 75-85% of the totalactive is released). In another embodiment, the ER beads are dried at arelative humidity of about 0-20%, including about 2-10% and about 4-8%at atmospheric pressure.

In addition, drying or curing times and temperatures can be varied, solong as the conditions produce ER beads having a desired drug releaseprofile. In one embodiment, the curing temperature is about 60° C.±5° C.Other curing temperatures such as about 50±5° C. may also be employed.Likewise, curing times may vary, including, for example, up to 24 hours,about 2-24 hours, about 2-12 hours, about 2-6 hours, and about 4 hours.In one embodiment, the ER beads are cured at about 60° C. for about 4hours. In another embodiment, the ER beads are cured at about 60° C. forabout 12 hours.

ER beads prepared as described above have a drug release profile, whentested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm)in 900 mL of 0.1 N HCl (or a suitable dissolution medium) at 37° C.,substantially corresponding to the following pattern (FIG. 2):

after 2 hours, no more than about 40% of the total active is released;

after 4 hours, from about 40-65% of the total active is released;

after 8 hours, from about 60-85% of the total active is released; and

optionally after 12 hours, from about 75-85% of the total active isreleased.

When IR beads are coated with the ER coating composition under coatingconditions (e.g., in a fluid bed coating apparatus) in which thetemperature and humidity are maintained to provide a dew point of about5-20° C., and optionally cured at a dew point of about 5-20° C. (e.g.,7-16° C.), the resulting ER beads show improved stability properties.For example, ER beads from commercial capsules, prepared in this mannerand packaged in bottles subjected to long term stability test conditions(e.g., at 25% RH after storage for up to 48 months) consistently providesubstantially uniform dissolution profiles when tested under in vitroconditions. In one embodiment, the ER beads thus prepared providedissolution profiles where the drug concentration does not deviate bynot more than 10% at any time point measured compared to the initialdissolution profile after about 3 months, 6 months, 12 months, 24months, 36 months, or 48 months of storage at. Extended release beadsthat are prepared using other processing conditions do not consistentlyexhibit comparable stability properties. For example, ER beads that areprepared by coating IR beads with an ER coating composition andoptionally cured under conditions in which the dew point is notcontrolled, or under an atmosphere outside the dew point range of about5-20° C. (e.g., 7-16° C.) do not consistently provide dissolutionprofiles that are stable throughout the expected duration of shelf-life(e.g., after 12 months, 24 months, 36 months, or up to 48 months storagein warehouses or pharmacies).

In addition, the uniformity of the release profile for ER beads in whichthe ER coating comprised a plasticizer was also found to depend on howthe ER coating solution was prepared. In one embodiment, the ER coatingis prepared by dissolving the water insoluble polymer (e.g., ethylcellulose) in a suitable solvent (e.g., an aqueous organic solvent suchas aqueous acetone), then adding the plasticizer to the solution andstirring the solution of water insoluble polymer and plasticizer for atleast one hour after addition of the plasticizer. In some embodiments,the solution of water insoluble polymer and plasticizer is stirred forat least about 2 hours, at least about 3 hours, at least about 4 hours,at least about 5 hours after the addition of the plasticizer. If thewater insoluble polymer and plasticizer solution is stirred for lessthan about one hour after the addition of the plasticizer, the resultingER beads do not consistently provide dissolution profiles that arestable over time (e.g., under storage conditions).

The cyclobenzaprine compositions prepared by the process of the presentinvention are useful for treating muscle spasms and the pain associatedwith muscle spasms, as well as fibromyalgia (a chronic syndromecharacterized by diffuse or specific muscle, joint, or bone pain,fatigue, and other symptoms) and as a sleep-aid.

The active core of the dosage form of the present invention may becomprised of an inert particle or an acidic or alkaline buffer crystal,which is coated with a drug-containing film-forming formulation andpreferably a water-soluble film forming composition to form awater-soluble/dispersible particle. Alternatively, the active may beprepared by granulating and milling and/or by extrusion andspheronization of a polymer composition containing the drug substance.The amount of drug in the core will depend on the dose that is required,and typically varies from about 5 to 60 weight %. Generally, thepolymeric coating on the active core will be from about 4 to 20% basedon the weight of the coated particle, depending on the type of releaseprofile required and/or the polymers and coating solvents chosen. Thoseskilled in the art will be able to select an appropriate amount of drugfor coating onto or incorporating into the core to achieve the desireddosage. In one embodiment, the inactive core may be a sugar sphere or abuffer crystal or an encapsulated buffer crystal such as calciumcarbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. whichalters the microenvironment of the drug to facilitate its release.

The drug-containing particle may be coated with an extended release (ER)coating comprising a water insoluble polymer or a combination of a waterinsoluble polymer and a water soluble polymer to provide ER beads. Inaccordance with certain embodiments, the water insoluble polymer and thewater soluble polymer may be present at a weight ratio of from 100/0 to65/35, more particularly from about 95/5 to 70/30, and still moreparticularly at a ratio of from about 85/15 to 75/25. The extendedrelease coating is applied in an amount necessary to provide the desiredrelease profile. The extended release coating typically comprises fromabout 1% to 15%, more particularly from about 7% to 12%, by weight ofthe coated beads.

The present invention also provides a method of making a modifiedrelease dosage form including a mixture of two bead populations. Inaccordance with one embodiment, the method includes the steps of:

-   -   preparing a drug-containing core by coating an inert particle        such as a non-pareil seed, an acidic buffer crystal or an        alkaline buffer crystal with a drug and a polymeric binder or by        granulation and milling or by extrusion/spheronization to form        an immediate release (IR) bead;    -   coating the IR bead with a water-insoluble polymer (optionally        plasticized) alone (such as ethylcellulose) or in combination        with a water soluble polymer (such as        hydroxypropylmethylcellulose) to form an Extended Release (ER)        bead;    -   filling into hard gelatin capsules ER Beads alone or in        combination with IR Beads at a proper ratio to produce MR        (modified release) capsules providing the desired release        profile.    -   IR beads when tested in accordance with the following procedure        release at least about 70%, more specifically at least about 90%        of the active within 30 minutes.

Dissolution Procedure:

Dissolution Apparatus: USP Apparatus 2 (Paddles at 50 rpm), dissolutionmedium: 900 mL 0.1N HCl (or a suitable dissolution medium) at 37° C. andDrug Release determination by HPLC).

An aqueous or a pharmaceutically acceptable solvent medium may be usedfor preparing drug-containing core particles. The type of film formingbinder that is used to bind the drug to the inert sugar sphere is notcritical but usually water soluble, alcohol soluble or acetone/watersoluble binders are used. Binders such as polyvinylpyrrolidone (PVP),polyethylene oxide, hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polysaccharides such as dextran, cornstarch may be used at concentrations from about 0.5 to 5 weight %,although other concentrations may be useful. The drug substance may bepresent in this coating formulation in the solution form or may bedispersed at a solid content up to about 35 weight % depending on theviscosity of the coating formulation.

Examples of appropriate polymers for coating applications include waxes,water-insoluble cellulose derivatives (e.g. ethylcellulose, ethers ofcellulose, esters of cellulose, cellulose acetate, cellulose butyrates,cellulose propionate, ethyl cellulose, mixed cellulose esters, etc),acylated polysaccharides, polyurethanes, polyvinyl acetate (e.g.,Kollicoat SR30D from BASF), polyacrylate and polymethacrylate polymersand derivatives, neutral copolymers comprising repeating units of ethylacrylate and/or methylmethacrylate, pH-insensitive ammonio methacrylicacid copolymers, copolymers of acrylic and methacrylic acid esters withquaternary ammonium groups, such as Eudragit NE, RS, RS30D, RL or RL30Dand the like, and combinations thereof. Preferred coating thicknessesrange from about 1 to about 1000 microns, most preferably between about20 to about 500 microns.

In accordance with certain embodiments, the drug substance, optionally abinder such as PVP, a dissolution rate controlling polymer (if used),and optionally other pharmaceutically acceptable excipients are blendedtogether in a planetary mixer or a high shear granulator such as Fielderand granulated by adding/spraying a granulating fluid such as water oralcohol. The wet mass can be extruded and spheronized to producespherical particles (beads) using an extruder/marumerizer. In theseembodiments, the drug load could be as high as 90% by weight based onthe total weight of the extruded/spheronized core.

Representative muscle relaxants include cyclobenzaprine, dantrolenesodium, methocarbamol, metaxalone, carisoprodol, diazepam andpharmaceutically acceptable salts, solvates, and/or esters thereof.Cyclobenzaprine hydrochloride is a particularly useful muscle relaxant.As used herein, the useful muscle relaxants include the base,pharmaceutically acceptable salts thereof such as hydrochloride,stereoisomers thereof and mixtures thereof.

Representative examples of water insoluble polymers useful in the ERcoating include waxes, ethylcellulose powder or an aqueous dispersion(such as AQUACOAT® ECD-30), cellulose acetate, polyvinyl acetate(Kollicoat SR#30D from BASF), neutral copolymers based on ethyl acrylateand methylmethacrylate, copolymers of acrylic and methacrylic acidesters with quaternary ammonium groups such as Eudragit NE, RS andRS30D, RL or RL30D and the like. Representative examples of watersoluble polymers useful herein include low molecular weighthydroxypropyl methylcellulose (HPMC), methylcellulose,hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol (PEGof molecular weight >3000) and mixtures thereof. The extended releasecoating will typically be applied at a thickness ranging from about 1weight % up to 15 weight % depending on the solubility of the active inwater and the solvent or latex suspension based coating formulationused.

The coating compositions used in forming the membranes are optionallyplasticized. Representative examples of plasticizers that may be used toplasticize the membranes include triacetin, tributyl citrate, triethylcitrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethyleneglycol, polypropylene glycol, castor oil, dibutyl-sebacate, acetylatedmonoglycerides and the like or mixtures thereof. The plasticizer maycomprise about 3 to 30 wt. % and more typically about 10 to 25 wt. %based on the polymer. The type of plasticizer and its content depends onthe polymer or polymers, nature of the coating system (e.g., aqueous orsolvent based, solution or dispersion based and the total solids).

In general, it is desirable to prime the surface of the particle beforeapplying an extended release membrane coating or to separate thedifferent membrane layers by applying a thin hydroxypropylmethylcellulose (HPMC) (OPADRY® Clear) film. While HPMC is typicallyused, other primers such as hydroxypropylcellulose (HPC) can also beused.

The membrane coatings can be applied to the core using any of thecoating techniques commonly used in the pharmaceutical industry, butfluid bed coating is particularly useful.

The present invention is applied to multi-dose forms, i.e., drugproducts in the form of multi-particulate dosage forms (pellets, beads,granules or mini-tablets) or in other forms suitable for oraladministration. As used herein, these terms are used interchangeably torefer to multi-particulate dosage forms.

The invention also provides a method of making an extended releasedosage form which includes a mixture of two or more bead populations. Inaccordance with one aspect of the present invention, the method includesthe steps of:

-   -   coating an inert particle such as a non-pareil seed, an acidic        buffer crystal or an alkaline buffer crystal with a drug and        polymeric binder to form an active drug particle (IR beads),        which may be present in the unit dosage form to act as a bolus        dose;    -   coating the active drug particle with a solution or suspension        of a water insoluble polymer or a mixture of water soluble and        water insoluble polymers to form an extended release coated drug        particle (ER beads);    -   filling into a hard gelatin capsule ER beads alone and        optionally, in combination with IR beads at a proper ratio        ranging from 95/5 to 70/30 (ER beads/IR beads) to produce a MR        (modified release) capsule exhibiting a target drug release        profile.

The methods of the present invention provide a modified release,multi-particulate dosage form of a skeletal muscle relaxant comprisingone or more bead populations which provides an extended release profileof the active under in vitro conditions closely mimicking the profilesimulated from pharmaco-kinetic modeling. At least one of the beadpopulations is an ER (extended release) bead population typicallycomprising a coating of a water insoluble polymer alone, or incombination with a water soluble polymer, applied onto active containingcores. The active core of the dosage form of the present invention maycomprise an inert particle such as a sugar sphere, or an acidic oralkaline buffer crystal, which is coated with a skeletal muscle relaxantsuch as cyclobenzaprine hydrochloride-containing film-formingformulation, preferably a water-soluble film forming composition. Thefirst coating formulation may contain, in addition to the active, abinder such as hydroxypropyl cellulose. The drug layered beads may becoated with a protective seal coating of OPADRY® Clear to produce IRBeads. Alternatively, the core particle may be formed by granulating anddry milling and/or by extrusion and spheronization of a pharmaceuticalcomposition containing the active. The amount of drug in the core willdepend on the dose required and typically varies from about 5 to about60% by weight.

ER Beads prepared by the methods of the present invention comprise afunctional membrane (e.g., extended release membrane) comprising a waterinsoluble polymer alone or in combination with a water soluble polymeronto IR Beads. The capsule formulation for once a day, oraladministration of a skeletal muscle relaxant prepared in accordance withthe present invention comprises ER Beads containing the active substanceand optionally IR Beads. IR (immediate release) Beads allow immediaterelease of the active while ER Beads allow an extended release profileof the active over several hours. Upon oral administration, such acapsule formulation provides for therapeutically effective plasmaprofiles over an extended period of time, thereby resulting in improvedpatient compliance.

The dosage forms prepared by the methods of the present inventioninclude one or more bead populations and provide a modified releaseprofile. At least one of the bead populations includes extended release(ER) beads wherein the ER beads include a core particle (IR (immediaterelease) bead) containing a skeletal muscle relaxant and an ER (extendedrelease) coating comprising a water insoluble polymer surrounding thecore. The dosage form, in accordance with certain embodiments, whendissolution tested using United States Pharmacopoeia Apparatus 2(paddles @ 50 rpm) in 900 mL of 0.1N HCl (or a suitable dissolutionmedium) at 37° C. exhibits a drug release profile substantiallycorresponding to the following pattern:

-   -   after 2 hours, no more than about 40% of the total active is        released;    -   after 4 hours, from about 40-65% of the total active is        released;    -   after 8 hours, from about 60-85% of the total active is        released; and    -   optionally after 12 hours, from about 75-85% of the total active        is released.

The dosage form thereby provides a therapeutically effective plasmaconcentration over an extended period of time, typically over a periodof 24 hours to treat muscle spasm associated with painfulmusculoskeletal conditions in humans. Alternatively, the dosage formsprepared by the methods of the present invention may be used to treatfibromyalgia or insomnia.

The following non-limiting examples illustrate the capsule dosage formsmanufactured in accordance with the invention using cyclobenzaprinehydrochloride as a test case, which exhibit in vitro drug releaseprofiles, similar to that predicted by performing modeling exercises.Such dosage forms when orally administered, would enable maintainingdrug plasma concentrations at therapeutically effective levels overextended periods of time, thereby significantly improving patientcompliance.

EXAMPLE 1

Cyclobenzaprine is well absorbed after oral administration, but there isa large intersubject variation in plasma levels. It is eliminated quiteslowly with a half-life as long as one to three days. The presenttreatment regimen of 10 mg three times daily is an issue of patientcompliance, especially the elderly. Hence, a modified release dosageform (capsule) was designed with a release profile shown in FIG. 1. Todetermine if this is the proper release profile, the pharmacokineticsdata of cyclobenzaprine following a single dose of 10 mg Flexeril®tablets administered 3 times a day was taken from the literature. Apharmacokinetic model was developed from this data using WinNonlin™Version 1.5.

The resulting model parameters are listed below:

Model Parameter Value Volume of Distribution/F 429 L K01 0.2031 hr⁻¹ K100.1004 hr⁻¹ K12 0.0828 hr⁻¹ K21 0.0398 hr⁻¹ Tlag 0 hr Dose 2 × 10 mgTablets

Theoretical plasma levels were simulated using the pharmacokinetic modelgiven above and the target release rate given in FIG. 1. FIG. 2 showsthe simulated plasma levels for day one following dosing of 1×10 mgFlexeril® Tablet given 3 times a day and the proposed CyclobenzaprineHCl MR Capsule, 30 mg given once a day.

EXAMPLE 2

A drug solution (25 wt. % solids) comprising cyclobenzaprinehydrochloride (1875.5 g) prepared in 50/50 acetone/purified water(2812.5 g each) and coated onto 20-25 mesh sugar spheres (5475 g) in aGlatt fluid bed coater, GPCG 5, equipped with a 9″ bottom spray Wurstertype “B” insert (14″ high), a partition height from the distributionplate of about 53 mm, at the following conditions: Nozzle diameter: 1.0mm; Room humidity: 64% RH; Atomization air pressure: 2.0-2.5 bar;Initial spray rate: 7 mL/min ramping up to about 60 mL/min; Producttemperature: 50±1° C.; Process air volume: about 150 CFM. After dryingat about 50° C. for 5 min, the resulting drug layered beads wereprovided with a protective seal coat of OPADRY® Clear at a coating levelof 2 wt. % in the Glatt fluid bed coater by spraying the aqueoussolution (10 wt. % solids) at a spray rate of about 8-10 g/min at aproduct temperature of 44° C., then dried at about 42° C. for 90 min toprovide “immediate release” (IR) beads.

An ER coating composition (30 wt. % solids) comprising Aquacoat ECD30(ethylcellulose aqueous dispersion) and Dibutyl sebacate (at 20% byweight) was then applied onto the IR Beads (spray rate of about 7-100mL/min, process air volume of 150 CFM) in a Glatt fluid bed coater toprovide an ER coating weight of 12% by weight. A 2 wt. % seal coat wasalso applied following completion of the ER coating. The seal coated ERbeads were dried in the unit at 46° C. for about 10 min to drive offresidual moisture. The sieved ER beads were cured at 60° C. for 12hours.

EXAMPLE 3

Cyclobenzaprine Hydrochloride (1,200 g) was slowly added to an aqueoussolution of polyvinylpyrrolidone such as Povidone USP (K-29/32, 80 g)and mixed well. # 20-25 mesh sugar spheres (2,640 g) were coated withthe drug solution in a Glatt fluid bed coater, equipped with a 9″ bottomspray Wurster insert to provide IR beads with a coating weight of about9%. The drug containing particles were dried, and a seal coat of OPADRY®Clear (2% w/w) was first applied and dried in the Glatt fluid bed unitas a precautionary measure to drive off excessive surface moisture. Thecomposition and batch quantities of the IR Beads were given in 5 to 10kg. Following the second coating process the IR Beads were passedthrough 14 and 24 mesh screens. Beads remaining on the 14-mesh screenwere discarded as oversized beads and beads passing through the 24-meshscreen were discarded as undersized beads.

The next step in the process was to apply an extended release polymermembrane by spraying AQUACOAT® ECD 30, an aqueous dispersion ofethylcellulose with dibutyl sebacate (76:24), onto the IR Beads for aweight gain of approximately 10%. The same fluid bed equipment was usedto produce ER (extended release) Beads by further coating the AQUACOAT®coated beads with OPADRY® Clear for a weight gain of 2% w/w prior tocuring at 60° C. in a conventional oven for a period of 24 hours. Thebatch size was 5 to 10 kg. The drug release profiles are shown in FIG.3. The figure also shows the drug release profiles from ER Beads storedin induction sealed HDPE bottles at 25° C./60% RH for 6 months.

EXAMPLE 4

Cyclobenzaprine Hydrochloride (2.5 kg) was dissolved in 50/50acetone/purified water. 20-25 mesh Sugar spheres, (7.3 kg) were coatedwith the drug solution in a Glatt fluid bed coater, equipped with a 9″bottom spray Wurster insert. The drug containing particles were dried,and a seal coat of OPADRY® Clear (2% w/w) was first applied and dried inthe Glatt fluid bed unit as a precautionary measure to drive offexcessive surface moisture. 910 g of ethylcellulose (Ethocel PremiumStandard 10 cps) and 90 g of diethyl phthalate were dissolved in 98/02acetone/purified water and applied onto the IR Beads (9 kg) in the GlattGPCG 5. The release rates of the ER Beads vary depending upon the filmweight of the ER coating. One batch of IR Beads was coated for a finalweight gain of 7% based on the weight of coated beads wherein samples ofthe ER Beads were removed during the ER coating process to yield beadswith increasing coating weights. Another batch was coated for 10% weightgain and all the coated bead batches were cured at 60° C. for 4 hours ina conventional oven. FIG. 4 shows the relationship between the ERcoating weights and the release rate of the finished ER coated Beads.

A batch was coated with a 7% ER coating and cured at 60° C. for 4 hours.No changes were noted in the release rates, assay values or impuritylevels after storage in HDPE bottles at 40° C./75% RH for a period of 6months. The release rates for the samples are shown in FIG. 5.

EXAMPLE 5

The drug layering, seal coating, and ER Coating processes were scaled-upto Glatt GPCG 120 equipped with an 18″ bottom spray Wurster insert(batch size: 80 kg for IR

Beads and 85 kg for ER Beads). The process parameters of each of theprocesses were optimized. The drug layering solution (25 wt. % solids),seal coating solution (8 wt. % solid), and the ER coating solution (6wt. % solids) were sprayed onto the sugar spheres or IR Beads whilemaintaining the product temperature between narrow limits. Following theseal or ER coating the beads were passed through 14 and 24 mesh screensdiscarding any beads remaining on the 14 mesh screen. The ER Beads werealso cured at 60° C. for a period of 4 hours. The Extended Release Beadswere then filled into size 4 capsules to produce Cyclobenzaprine HCl MRCapsules, 15 and 30 mg. The drug release profiles of 30 mg capsules ofone pivotal clinical and three registration stability batches arepresented in FIG. 6.

EXAMPLE 6

A randomized double-blind two-period crossover study to assess thesafety and bioavailability of Cyclobenzaprine HCl Modified-release (CMR)15 mg and 30 mg in healthy male and female volunteers (N=14 or 15) wasperformed. Each subject received one 15 mg or 30 mg capsule of CMR inthe morning, separated by a 14-day washout period between doses. Theresults are presented in Table 1 and FIG. 7 wherein AUC₀₋₁₆₈ refers tothe area under the plasma concentration-time curve to the lastmeasurable time point (168 hrs) calculated by the linear trapezoidalrule, AUC_(0-∞) refers to area under the concentration-time curve toinfinity, C_(max) refers to the maximum blood plasma concentration andT_(max) refers to the time to maximum plasma levels of cyclobenzaprine.

TABLE 1 Pharmacokinetic Results: Mean (± SD) pharmacokinetic parametersare presented for subjects in the Safety population in the followingtable CMR 15 mg CMR 30 mg N = 15 N = 14 AUC₀₋₁₆₈ (ng · hr/mL) 318.30 ±114.657 736.60 ± 259.414 AUC_(0-∝) (ng · hr/mL) 354.075 ± 119.8037779.889 ± 277.6349 C_(max) (ng/mL) 8.315 ± 2.1635 19.851 ± 5.8765 Timeto Peak, T_(max) (hr) 8.1 ± 2.94 7.1 ± 1.59 Elimination Half-life,t_(1/2) (hr) 33.401 ± 10.2882 31.977 ± 10.1310

The treatments were significantly different from each other as valuesfor AUCs and C_(max) were higher for CMR 30 mg than those for CMR 15 mg.The bioavailability of CMR 30 mg was approximately twice that of CMR 15mg as shown by the AUCs. The adjusted mean ratio of CMR 30 mg to CMR 15mg was greater than about 2 for each of the AUCs and C_(max),specifically the calculated values were 2.42 for AUC₀₋₁₆₈ (p<0.001),2.286 for AUC_(0-∞) (p<0.001), and 2.424 for C_(max)(p<0.001). Overall,both CMR 15 mg and 30 mg were well tolerated during the study.

Accordingly, one aspect of the invention relates to a dosage formcontaining cyclobenzaprine hydrochloride as a skeletal muscle relaxantwherein the pharmaceutical dosage form provides a maximum blood plasmaconcentration (C_(max)) within the range of about 80% to 125% of about20 ng/mL of cyclobenzaprine HCl, an AUC₀₋₁₆₈ within the range of about80% to 125% of about 740 ng·hr/mL and a T_(max) within the range ofabout 80% to 125% of about 7 hours following oral administration of asingle 30 mg cyclobenzaprine HCl MR Capsule.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made without departingfrom the spirit and scope thereof.

1. A method of preparing a pharmaceutical composition comprising: a)coating about 20-25 mesh inert particles with a drug layeringcomposition comprising cyclobenzaprine or a pharmaceutically acceptablesalt, solvate, and/or ester thereof, and a pharmaceutically acceptablesolvent; b) drying the coated inert particles, thereby forming druglayered beads; c) coating the drug layered beads with a seal coatingcomposition comprising a pharmaceutically acceptable water solublepolymer and water; d) drying the coated drug layered beads, therebyforming IR beads; and e) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads.
 2. The method of claim 1, furthercomprising: f) curing the ER beads at about 60° C. for about 4-12 hoursunder an atmosphere having a dew point ranging from about 5-20° C. 3.The method of claim 1, wherein the ER coating composition furthercomprises a plasticizer.
 4. The method of claim 3, wherein the ERcoating composition is prepared by stirring the pharmaceuticallyacceptable water-insoluble polymer, plasticizer and pharmaceuticallyacceptable solvent for at least about 1 hour after addition of theplasticizer to the pharmaceutically acceptable water-insoluble polymerand pharmaceutically acceptable solvent.
 5. The method of claim 4,wherein the pharmaceutically acceptable water-insoluble polymer,plasticizer and pharmaceutically acceptable solvent are stirred for atleast about 3 hours after addition of the plasticizer to thepharmaceutically acceptable water-insoluble polymer and pharmaceuticallyacceptable solvent.
 6. The method of claim 1, wherein the drug layeringcomposition comprises cyclobenzaprine hydrochloride and about 50:50acetone:water.
 7. The method of claim 1, wherein the pharmaceuticallyacceptable water soluble polymer comprises hydroxypropylmethylcellulose.
 8. The method of claim 1, wherein the pharmaceuticallyacceptable water-insoluble polymer is selected from the group consistingof ethylcellulose, ethers of cellulose, esters of cellulose, celluloseacetate, cellulose butyrate, cellulose propionate, polyvinyl acetate,neutral copolymers based on ethyl acrylate and methyl methacrylate,copolymers of acrylic and methacrylic acid esters with quaternaryammonium groups, pH-insensitive ammonio methacrylic acid copolymers,waxes, acetylated polysaccharides, polyurethanes, high molecular weighthydroxypropyl methylcellulose, polyacrylate and polymethacrylatepolymers, and mixtures thereof.
 9. The method of claim 1, wherein thepharmaceutically acceptable water insoluble polymer comprisesethylcellulose.
 10. The method of claim 3, wherein the plasticizer isselected from the group consisting of diethyl phthalate, triacetin,tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, dibutylsebacate, polyethylene glycol, polypropylene glycol, castor oil,acetylated mono- and di-glycerides, glyceryl monostearate, glyceryltriacetate, glyceryl tributyrate, phthalates, citrates,glyceroltributyrate; sebacates, adipates, azelates, benzoates,chlorobutanol, polyethylene glycols, vegetable oils, olive oil, castoroil, mineral oil, fumarates, malates, oxalates, succinates, butyrates,cetyl alcohol esters, malonates, polysorbates, glycerine,N-butylbenzenesulfonamide, N-methylpyrrolidone, and mixtures thereof.11. The method of claim 3, wherein the plasticizer comprises diethylphthalate.
 12. The method of claim 3, wherein the ER coating compositioncomprises ethylcellulose and diethyl phthalate dissolved in a solventcomprising acetone and water at a acetone/water weight ratio rangingfrom about 85/15 to about 98/2.
 13. The method of claim 3, wherein theratio of water-insoluble polymer to plasticizer is about 9:1.
 14. Themethod of claim 1, wherein the drug layering composition comprisescyclobenzaprine hydrochloride, and after drying, the drug layered beadscomprise from about 20 wt. % to about 30 wt. % cyclobenzaprinehydrochloride.
 15. The method of claim 14, wherein the drug layeringcomposition comprises cyclobenzaprine hydrochloride, and after drying,the drug layered beads comprise about 25 wt. % cyclobenzaprinehydrochloride.
 16. The method of claim 1, wherein the IR beads compriseabout 2% of the pharmaceutically acceptable water soluble polymer. 17.The method of claim 1, wherein the ER beads comprise about 7% to about12% of the pharmaceutically acceptable water insoluble polymer.
 18. Themethod of claim 2, wherein the ER beads comprise about 9% of thepharmaceutically acceptable water-insoluble polymer and plasticizer. 19.The method of claim 1, wherein said coating step e) is carried out at adew point of about 6-17° C.
 20. The method of claim 1, wherein the ERbeads provide a drug release profile that does not deviate by more thanabout 10% at any time point in the following dissolution pattern: after2 hours, no more than about 40% of the total active is released; after 4hours, from about 40-65% of the total active is released; after 8 hours,from about 60-85% of the total active is released; and optionally after12 hours, from about 75-85% of the total active is released, when testedusing United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900mL of 0.1 N HCl (or a suitable dissolution medium) at 37° C.
 21. Themethod of claim 1, wherein the ER beads provide a drug release of about20% to about 50% after 2 hours when tested using United StatesPharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of 0.1 N HCl (ora suitable dissolution medium) at 37° C.